1. Field of the Invention
This invention relates to articles of manufacture and to methods for the subungual (under the nail) treatment of infections, especially fungal infections, of the toenails and fingernails (onychomycosis).
2. The State of the Art
Fungi are eukaryotic cells that may reproduce sexually or asexually and may be biphasic, with one form in nature and a different form in the infected host. Fungal diseases are referred to as mycoses.
A fungal infection of the nails, commonly referred to as onychomycosis, is most frequently caused by dermatophytes (most commonly Trichophyton rubrum) but also can be caused by molds and Candida. Mixed infections also occur. There are several forms of onychomycosis: distal lateral subungual (DLSUO), white superficial, proximal subungual, endonyx, and candidal. The most common form is DLSUO in which the fungus spreads from the plantar skin and invades the underside of the nail via the hyponychium and distal lateral nail bed. Inflammation involving these areas produces the characteristic signs of the disease including a thickened and discolored nail plate, nail bed hyperkeratosis, and onycholysis (a separation or loosening of the nail plate from the nail bed which starts at the distal free margin and progresses proximally as the infection moves proximally). Onychomycosis may cause pain and discomfort especially (in the case of toenail DLSUO) with standing, walking, and exercise, some loss of dexterity (in the case of fingernail DLSUO), and is often associated with embarrassment and diminished self-esteem. The onychomycotic nail also serves as a reservoir for dermatophytes and contributes to treatment failure and recurrence of tinea pedis. 
The majority of known antifungal agents fall into one of three main groups. One major group includes polyene derivatives, including amphotericin B and the structurally related compounds nystatin and pimaricin, which are only administered intravenously. The unrelated antifungal agent flucytosine (5-fluorocytosine, a diazine), an orally absorbed drug, is frequently used as an adjunct to amphotericin B treatment for some forms of candidiasis and cryptococcal meningitis.
A second major group of antifungal agents is the azole derivatives. This group of agents includes ketoconazole (U.S. Pat. Nos. 4,144,346 and 4,223,036), fluconazole (U.S. Pat. No. 4,404,216), itraconazole (U.S. Pat. No. 4,267,179), voriconazole, bifonazole, clotrimazole, miconazole, econazole, butoconazole, oxiconazole, sulconazole, terconazole, liarozole, and irtemazol. U.S. Pat. No. 6,277,873 describes substituted thiazole, thiadiazole, and oxadiazole antifungals.
A third major group of antifungal agents includes the fungicidal allylamines such as naftifine (Naftin), terbinafine (EP 24,587-A1; Lamisil), and the benzylamine butenafine (Mentax).
Various other types of antifungal agents are known. Griseoflulvin is a fungistatic agent which is administered orally for fungal infections of skin, hair or nails that do not respond to topical treatment. Still other antifungal agents include thiocarbonate tolnaftate, ciclopirox, sulbentine, and morpholines, e.g., amorolfine, and the related morpholines disclosed in U.S. Pat. No. 5,120,530, and the 1-hydroxy-2-pyridone compounds disclosed in U.S. Pat. No. 4,957,730. Like the allylamines and azoles, tolnaftate blocks synthesis of ergosterol.
It has also been known to combine antifungal agents with anti-inflammatory agents. The steroidal anti-inflammatory agent may be selected from among any of the known steroidal anti-inflammatory agents, including, for example, any of those disclosed in The Merck Index or in U.S. Pat. Nos. 5,002,938, 5,110,809, and 5,219,877. Examples of steroidal anti-inflammatory agents useful in combination with antifungals can include 21-acetoxypregnenolone, alclometasone or its dipropionate salt, algestone, amcinonide, beclomethasone or its dipropionate salt, betamethasone and salts thereof, including, for example, betamethasone benzoate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone sodium phosphate and acetate, and betamethasone valerate; clobetasol or its propionate salt, clocortolone pivalate, hydrocortisone and salts thereof, including, for example, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone cypionate, hydrocortisone phosphate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone tebutate and hydrocortisone valerate; cortisone acetate, desonide, desoximetasone, dexamethasone and salts thereof, for example, acetate and sodium phosphate; diflorasone diacetate, fludrocortisone acetate, flunisolide, fluocinolone acetonide, fluocinonide, fluorometholone, flurandrenolide, halcinonide, medrysone, methylprednisolone and salts thereof, e.g., acetate, sodium succinate; mometasone furoate, paramethasone acetate, prednisolone and salts thereof, e.g., acetate, diethylaminoacetate, sodium phosphate, sodium succinate, tebutate, trimethylacetate; prednisone, triamcinolone and derivatives thereof, e.g., acetonide, benetonide, diacetate, hexacetonide. Other glucocorticoid steroids reported in the literature, including The Merck Index, or otherwise approved by the local drug regulatory agency, e.g., Food and Drug Administration, may also be used. Preferred steroidal anti-inflammatory agents usually include clobetasol and its salts, e.g., propionate salt; betamethasone and its salts, hydrocortisone and its salts, and triamcinolone and its salts, although as new steroidal anti-inflammatories are developed and reviewed, preferences may change. The anti-inflammatory agent will usually be present in a topical composition in combination with an antifungal in an amount within the range of 0.01 to about 5 percent, preferably from about 0.1 to 2 percent, based on the total weight of the composition.
Thus, various types of antifungal agents and their combination with steroidal anti-inflammatory agents are known.
In spite of the wide varieties of anti-fungal that are available and their use in combination with other active ingredients, onychomycosis is difficult to treat. Since on most ocassions onychomycosis (i.e., the distal lateral subungual form) is a disease of the nail bed underlying the nail plate, the condition is best treated systemically (“from the inside”) because topical access to the nail bed is restricted by the relatively impermeable nail plate. Consequently, onychomycosis can be treated effectively in many patients using systemic (oral) medications such as terbinafine (Lamisil) and itraconazole (Sporonox). Fluconazole (Diflucan), although not FDA approved, is also used in some patients. These newer drugs have supplanted oral forms of ketoconazole and griseofulvin, which were previously used to treat the disease. However the systemic (oral) medicines must be administered for several months for elimination of the infection and regrowth of new nail. These drugs may also produce serious side effects, and they may interact with other medications. Accordingly, systemic medications for treating onychomycosis are unacceptable for many patients. For those patients, the only available route of administration is topical.
Nail lacquers for the treatment of onychomycoses and similar fungal infections affecting nails (toe nails and/or finger nails) of humans, in particular, or other animals, are known. Representative examples are described in the patent literature, such as the following U.S. Pat. No. 4,957,730 (1-hydroxy-2-pyridone in water-insoluble film-former); U.S. Pat. No. 5,120,530 (amorolfine in quaternary ammonium acrylic copolymer); U.S. Pat. No. 5,264,206 (tioconazole, econazole, oxiconazole, miconazole, tolnaftate, naftifine hydrochloride, in water-insoluble film-former); U.S. Pat. No. 5,346,692 (with urea and dibutyl phthalate plasticizer); U.S. Pat. No. 5,487,776 (griseofulvin as colloidal suspension). U.S. Pat. No. 6,224,887, teaches a nail lacquer for onychomycosis with the combination of antifungal and a certain penetration-enhancing medium carbon chain dioxane or acetal. PENLAC brand ciclopirox is the only FDA-approved topical treatment approved in the United States for onychomycosis. Topical products approved for use outside of the United States include a lacquer of amorolfine and a combination of bifonazole
Other U.S. Pat. Nos. which relate to antifungal products include, for example: U.S. Pat. No. 4,636,520 (combination of imidazole and pyrrolnitrin); U.S. Pat. No. 5,002,938 (gel, combination of imidazole and 17-ester corticosteroid anti-inflammatory agent); 5,110,809 (antifungal gel plus steroid); U.S. Pat No. 5,219,877 (gel product with imidazole antifungal optionally with steroidal anti-inflammatory, in a vehicle system that includes lauryl alcohol); U.S. Pat. No. 5,391,367 (aqueous alcoholic gel with tioconazole); U.S. Pat. No. 5,464,610 (salicylic acid plaster); and U.S. Pat. No. 5,696,105 (mometasone furoate).
U.S. Pat. No. 6,207,142 describes antifungal shampoos.
U.S. Pat. No. 5,894,020, discloses an antifungal bar soap for treating tinea pedis. 
Anatomically, the “nail” that is seen is technically the nail plate. At the most proximal end is the matrix (root), from which the nail grows, and the eponychium (the cuticle) which forms a seal between the skin and the nail plate. At the distal end, between the nail plate and the skin, is the hyponychium. The nail plate presents a considerable barrier to penetration and hence limits access to the nail bed for products applied topically to the nail plate. Current topical therapies have such low penetration through the nail plate that they have a very low efficacy (less than 10% even after prolonged application). These therapies do not appear to exhibit characteristic concentration-response or time-response relationships. This suggests that in the small percentage of people in whom these topical treatments are effective, efficacy may not be related to penetration through the nail. Materials such as urea increase the penetration of the medication through the nail plate, but such materials alter the nail and disrupt its integrity.